Advances in antiretroviral therapy (ART) have resulted in increased survival of the HIV-infected population; however, this gain in longevity is associated with an increased risk of cardiovascular disease (CVD). Causal mechanisms of increased CVD remain elusive, but heightened markers of immune activation, inflammation, and coagulation are highly associated, suggesting that therapeutic strategies aimed at modulating these systems may decrease CVD in this population. Platelets lie at the intersection of immunity, inflammation and thrombosis. Platelets initiate thrombus formation and also play a key role in vascular inflammation, through release of pro-inflammatory mediators and interactions with other relevant cell types. We and others have shown that platelets are hyper- activated in chronic HIV infection. Importantly, we demonstrated that one week of low-dose aspirin therapy significantly decreased platelet activation and plasma markers of immune activation, and caused a trend of decreased levels of inflammatory plasma markers. Aspirin inhibits platelet aggregation by inactivating the cyclooxygenase enzyme to block thromboxane A2 synthesis, but it also has pleiotropic anti-inflammatory and immune-modulatory effects. Therefore, we do not know whether aspirin therapy decreased immune activation 1) indirectly through inhibition of platelet activation and platelet-leukocyte interactions or 2) directly throug blocking inflammatory pathways in multiple cell types. Aspirin's beneficial effects on HIV-related immune activation and inflammation are more likely indirect, through platelet-inhibition, because the low dose of aspirin used in our pilot study is less likely to directly affect inflammatory pathways in immune cells. The hypothesis of this study is that anti-platelet therapy, regardless of the mechanism of platelet inhibition, will significantly decrease immune activation and inflammation, potentially contributing to a reduction in the risk of CVD in this population. Clopidogrel is an anti-platelet therapy that is similarly potent to aspirin, but inhibits platelet aggregation through a different mechanism of action by blocking the adenosine diphosphate chemoreceptor P2Y12. To test this hypothesis we will conduct a prospective, double- blind, randomized, placebo-controlled 3-arm clinical trial in ART-treated HIV infected subjects to compare aspirin 81 mg to clopidogrel 75 mg to placebo to be given for 24 weeks. Concurrent with the trial, we will perform laboratory-based studies to improve the understanding of mechanisms by which anti-platelet therapy attenuates immune activation and inflammation in treated HIV disease. A secondary hypothesis is that platelet activation drives blood thrombogenicity in HIV-infected patients, and that HIV-infected patients with the highest levels of platelet activation will also have the highest degree of blood thrombogenicity. (End of Abstract)